SIOC 中文
CJOG
Adv search

Chinese Journal of Organic Chemistry >

2020 , Vol. 40 >Issue 11: 3828 - 3836

DOI: https://doi.org/10.6023/cjoc202006059

Insights into the Substrate Tolerance of Enzymes Involved in the Nosiheptide Biosynthesis Pathway Based on Indolic Acid Moiety

  • Fan Yafei ,
  • Zhang E ,
  • Guo Heng ,
  • Mu Ning ,
  • Chen Dandan ,
  • Wang Wengui ,
  • Wang Shoufeng ,
  • Liu Wen
Expand
  • a Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022;
    b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032;
    c Huzhou Center of Bio-Synthetic Innovation, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Huzhou, Zhejiang 313000

Received date: 2020-06-28

  Revised date: 2020-08-06

  Online published: 2020-09-09

Supported by

Project supported by the National Natural Science Foundation of China (Nos. 31972850, 21750004, 21520102004), the Shandong Key Research Program (No. 2019GSF108223), the Chinese Academy of Sciences (Nos. QYZDJ-SSW-SLH037, XDB20020200), the Science and Technology Commission of Shanghai Municipality (No. 17JC1405100), the Youth Innovation Promotion Association of the Chinese Academy of Sciences (No. 2017303), the State Key Laboratory of Microbial Technology Open Projects Fund (No. M2020-05) and the K. C. Wong Education Foundation.

Fold

Abstract

As a typical representative of thiopeptide antibiotics, nosiheptide (NOS) possesses very good antibacterial activity. However, due to poor water solubility and low bioavailability, its clinical application is hampered. Due to its complex structure, it is difficult to obtain analogues with improved physical and chemical properties via total chemical synthesis. Based on the previous studies on the biosynthesis of nosiheptide, the side-ring 3-methyl-2-indoleic acid (MIA) analogues were used as chemical small molecule probes to explore the substrate tolerance of enzymes involved in NOS biosynthesis pathway in NOS-producing bacteria via the co-fermentation of probe molecules with mutant strain and the combination of high resolution mass spectrometry data of fermentation products. The results showed that enzymes involved in NOS biosynthesis pathway had a considerable tolerance to MIA analogues substituted by F, Cl and CH3, however, MIA analogues substituted by large steric hindrance group, such as NO2, CF3 and Ph, were not tolerated. The position, the size and the property of the substituted groups of MIA also affected the steps of identification, transport and upload of the related enzymes involved in NOS biosynthesis. The present study not only explored the substrate tolerance of enzymes involved in NOS biosynthesis pathway, but also was expected to obtain NOS analogues via biosynthetic pathway engineering. What’s more, it provides valuable information for using directed evolution technology to improve the substrate tolerance of enzymes in the rate-limiting steps of NOS biosynthesis and to expand the use of NOS-producing bacteria to obtain more analogues.

Key words： nosiheptide; 3-methyl-2-indolic acid; mutational biosynthesis; chemical small molecule probe; substrate tolerance of enzymes

Cite this article

Fan Yafei , Zhang E , Guo Heng , Mu Ning , Chen Dandan , Wang Wengui , Wang Shoufeng , Liu Wen . Insights into the Substrate Tolerance of Enzymes Involved in the Nosiheptide Biosynthesis Pathway Based on Indolic Acid Moiety[J]. Chinese Journal of Organic Chemistry, 2020 , 40(11) : 3828 -3836 . DOI: 10.6023/cjoc202006059

References

[1] Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2020, 83, 770.
[2] Just-Baringo, X.; Albericio, F.; Alvarez, M. Angew. Chem., Int. Ed. 2014, 53, 6602.
[3] Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X. Chem. Rev. 2005, 105, 685.
[4] Haste, N. M.; Thienphrapa, W.; Tran, D. N.; Loesgen, S.; Sun, P.; Nam, S.; Jensen, P. R.; Fenical, W.; Sokoulas, G.; Nizet, V.; Hensler, M. E. J. Antibiotics 2012, 65, 593.
[5] Harms, J. M.; Wilson, D. N.; Schluenzen, F.; Connell, S. R.; Stachelhaus, T.; Zaborowska, Z.; Spahn, C. M. T.; Fucini, P. Mol. Cell 2008, 30, 26.
[6] Wison, D. N. Nat. Rev. Microbiol. 2014, 12, 35.
[7] Wojtas, K. P.; Riedrich, M.; Lu, J. Y.; Winter, P.; Winkler, T.; Walter, S.; Arndt, H. D. Angew. Chem., Int. Ed. 2016, 55, 9772.
[8] Arnison, P. G.; Bibb, M. J.; Bierbaum, G.; Bowers, A. A.; Bugni, T. S.; Bulaj, G.; Camarero, J. A.; Campopiano, D. J.; Challis, G. L.; Clardy, J.; Cotter, P. D.; Craik, D. J.; Dawson, M.; Dittmann, E.; Donadio, S.; Dorrestein, P. C.; Entian, K. D.; Fischbach, M. A.; Garavelli, J. S.; Goransson, U.; Gruber, C. W.; Haft, D. H.; Hemscheidt, T. K.; Hertweck, C.; Hill, C.; Horswill, A. R.; Jaspars, M.; Kelly, W. L.; Klinman, J. P.; Kuipers, O. P.; Link, A. J.; Liu, W.; Marahiel, M. A.; Mitchell, D. A.; Moll, G. N.; Moore, B. S.; Muller, R.; Nair, S. K.; Nes, I. F.; Norris, G. E.; Olivera, B. M.; Onaka, H.; Patchett, M. L.; Piel, J.; Reaney, M. J.; Rebuffat, S.; Ross, R. P.; Sahl, H. G.; Schmidt, E. W.; Selsted, M. E.; Severinov, K.; Shen, B.; Sivonen, K.; Smith, L.; Stein, T.; Sussmuth, R. D.; Tagg, J. R.; Tang, G. L.; Truman, A. W.; Vederas, J. C.; Walsh, C. T.; Walton, J. D.; Wenzel, S. C.; Willey, J. M.; van der Donk, W. A. Nat. Prod. Rep. 2013, 30, 108.
[9] Yu, Y.; Duan, L.; Zhang, Q.; Liao, R. J.; Ding, Y.; Pan, H. X.; Wendt-Pienkowski, E.; Tang, G. L.; Shen, B.; Liu, W. ACS Chem. Biol. 2009, 4, 855.
[10] Qiu, Y. P.; Du, Y. A.; Zhang, F.; Liao, R. J.; Zhou, S. X.; Peng, C.; Guo, Y. L.; Liu, W. J. Am. Chem. Soc. 2017, 139, 18186.
[11] Bhandari, D. M.; Fedoseyenko, D.; Begley, T. P. J. Am. Chem. Soc. 2018, 140, 542.
[12] Zhang, Q.; Li, Y. X.; Chen, D. D.; Yu, Y.; Duan, L. A.; Shen, B.; Liu, W. Nat. Chem. Biol. 2011, 7, 154.
[13] Badding, E. D.; Grove, T. L.; Gadsby, L. K.; LaMattina, J. W.; Boal, A. K.; Booker, S. J. J. Am. Chem. Soc. 2017, 139, 5896.
[14] Ding, W.; Ji, W. J.; Wu, Y. J.; Wu, R. Z.; Liu, W. Q.; Mo, T. L.; Zhao, J. F.; Ma, X. Y.; Zhang, W.; Xu, P.; Deng, Z. X.; Tang, B. P.; Yu, Y.; Zhang, Q. Nat. Commun. 2017, 8, 437.
[15] LaMattina, J. W.; Wang, B.; Badding, E. D.; Gadsby, L. K.; Grove, T. L.; Booker, S. J. J. Am. Chem. Soc. 2017, 139, 17438.
[16] Wang, B.; LaMattina, J. W.; Marshall, S. L.; Booker, S. J. J. Am. Chem. Soc. 2019, 141, 5788.
[17] Qiu, Y. P.; Du, Y. N.; Wang, S. F.; Zhou, S. X.; Guo, Y. L.; Liu, W. Org. Lett. 2019, 21, 1502.
[18] Hudson, G. A.; Zhang, Z. G.; Tietz, J. I.; Mitchell, D. A.; van der Donk, W. A. J. Am. Chem. Soc. 2015, 137, 16012.
[19] Cogan, D. P.; Hudson, G. A.; Zhang, Z. G.; Pogorelov, T. V.; van der Donk, W. A.; Mitchell, D. A.; Nair, S. K. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 12928.
[20] Wever, W. J.; Bogart, J. W.; Baccile, J. A.; Chan, A. N.; Schroeder, F. C.; Bowers, A. A. J. Am. Chem. Soc. 2015, 137, 3494.
[21] Yu, Y.; Guo, H.; Zhang, Q.; Duan, L. A.; Ding, Y.; Liao, R. J.; Lei, C.; Shen, B.; Liu, W. J. Am. Chem. Soc. 2010, 132, 16324.
[22] Liu, W. Y.; Xue, Y. J.; Ma, M.; Wang, S. Z.; Liu, N.; Chen, Y. J. ChemBioChem 2013, 14, 1544.
[23] Kennedy, J. Nat. Prod. Rep. 2008, 25, 25.
[24] Zhang, E.; Guo, H.; Chen, D. D.; Yang, Q.; Fan, Y. F.; Yin, Y.; Wang, W. G.; Chen, D. J.; Wang, S. F.; Liu, W. Org. Biomol. Chem. 2020, 18, 4051.
[25] Bratsch, S. G. J. Chem. Educ. 1985, 62, 101.
[26] Gan, T.; Liu, R.; Yu, P.; Zhao, S.; James M, C. J. Org. Chem. 1997, 62, 9298.
[27] Arai, M.; Yamazaki, T.; Tamaki, K. WO 113499, 2005.
[28] Jane, C. E.; Stacy, G. L.; Bryan, M. N.; Shi, Q.; Wang, M.; Alan M, W.; Xu, Y. WO 054176, 2005.
[29] Cai, Q.; Li, Z. Q.; Wei, J. J.; Ha, C. Y.; Pei, D. Q.; Ding, K. Chem. Commun. 2009, 7581.
[30] Piscitelli, F.; Ligresti, A.; Regina, G. L.; Coluccia, A.; Morera, L.; Allara, M.; Novellino, E.; Marzo, V. D.; Silvestri, R. J. Med. Chem. 2012, 55, 5627.
[31] Kim, Y. A.; Han, S. Y. Synth. Commun. 2004, 34, 2931.
Options
Outlines

/

〈 〉